Research progress of traditional Chinese medicine monomer in treating diabetic peripheral neuropathy: A review

Diabetes peripheral neuropathy is one of the most common complications of diabetes. Early symptoms are insidious, while late symptoms mainly include numbness, pain, swelling, and loss of sensation in the limbs, which can lead to disability, foot ulcers, amputation, and so on. At present, the pathogenesis is also complex and diverse, and it is not yet clear. Western medicine treatment mainly focuses on controlling blood sugar and nourishing nerves, but the effect is not ideal. In recent years, it has been found that many drug monomers have shown good therapeutic and prognostic effects in the prevention and treatment of diabetes peripheral neuropathy, and related research has become a hot topic. To understand the specific mechanism of action of traditional Chinese medicine monomers in treatment, this article provides a review of their mechanism research and key roles. It mainly includes flavonoids, phenols, terpenes, saponins, alkaloids, polysaccharides, etc. By nuclear factor-κB (NF-κB), the signaling pathways of adenosine monophosphate-activated protein kinase (AMPK), Nrf2/ARE, SIRT1/p53, etc, can play a role in lowering blood sugar, antioxidant, anti-inflammatory, inhibiting cell apoptosis, and autophagy, promoting sciatic nerve regeneration, and have great potential in the prevention and treatment of this disease. A systematic summary of its related mechanisms of action was conducted, providing ideas for in-depth research and exploration of richer traditional Chinese medicine components, and also providing a relatively complete theoretical reference for clinical research on diabetes peripheral neuropathy treatment.


Introduction
Diabetes peripheral neuropathy (DPN) is a kind of diabetes neuropathy.Epidemiological studies have found that by 2030, the number of diabetes patients will reach 578 million, and after 15 years, the number of affected people will reach 700 million, [1] and more than 50% of diabetes patients will develop into DPN.The most common type is distal symmetric polyneuropathy, which is mainly characterized by loss of sensation in the limbs.If not treated in time in the early stage, it is easy to face the risk of infection, or even amputation, which will seriously affect the quality of life of diabetes patients.At present, there are no specific effective drugs available.The existing drugs mainly focus on controlling blood sugar, nourishing nerves, controlling metabolic syndrome, and relieving pain. [2]owever, most treatments can only alleviate the symptoms of patients and fail to fundamentally solve the problem.Therefore, it is urgent to find safe and effective treatment drugs.Compared with Western medicine, traditional Chinese medicine has the characteristics of multiple targets, multiple components, and multiple pathways.In recent years, the government has increased its support for the traditional Chinese medicine industry, and more and more research has been conducted on the use of traditional Chinese medicine monomers to treat DPN.This article summarizes the basic and clinical research of common traditional Chinese medicine monomers for treating DPN, providing a reference for further exploring its pathogenesis and clinical medication.

Flavonoids
Modern studies have reported that flavonoids have antiinflammatory, antioxidant, and blood sugar control effects.Puerarin is the main active extract of Pueraria lobata and an isoflavone compound.Xue et al [3] found that puerarin protects tissue cells from damage by inhibiting cell apoptosis and oxidative stress, which is related to its inhibition of activation of apoptosis-related proteins (including caspase-3), downregulation of bcl-2, and upregulation of Bax.Zhao et al [4] confirmed that quercetin can improve the mechanical threshold, sciatic nerve conduction velocity, and pathological changes of the sciatic nerve in diabetes rats, possibly by downregulating TLR4/MyD88/NF-κB signaling pathway to reduce the level of inflammatory factors in diabetes rats.Park et al [5] found that baicalin inhibits excessive reactive oxygen species (ROS) and blocks hydrogen peroxide (H 2 O 2 ) induced apoptosis and DNA damage in RT4-D6P2T Schwann cells, indicating that baicalin can protect Schwann cells from oxidative stress.Li et al [6] found through animal experiments that luteolin can reduce the levels of ROS and malondialdehyde in the blood of mice to a certain extent.This experiment showed that luteolin can resist oxidation and alleviate peripheral nerve damage in DPN rats.In addition, it was found that luteolin upregulates the expression of Nrf2 and HO-1 (a phase II detoxifying enzyme) by activating the Nrf2 pathway.This series of antioxidant mechanisms can balance nerve damage caused by free radicals, thereby achieving a protective effect on nerves.Kishore et al [7] found that kaempferol can correct hyperglycemia and partially reverse the pain response of diabetes rats by regulating oxidative and nitrous stress and reducing the formation of AGEs in diabetes rats.Naringenin is a natural flavonoid with neuroprotective activity.Naringenin is a natural flavonoid with neuroprotective activity.Semis et al [8] have shown that naringenin can alleviate peripheral neuropathy caused by oxaliplatin, and its mechanism of action is related to improving SOD, CAT, Glutathione peroxidase (GPx), Nrf2, HO-1, TNF-α, etc. Another study suggests that naringin is expressed through AMPK-α And PKC-δ.The pathway activates cytokine signaling (SOCS)-3 in microglia to inhibit the expression of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines. [9]

Polyphenols
Turmeric is the root of the herb ginger, and curcumin is a chemical extract of turmeric.[12] Curcumin inhibits astrocyte proliferation, microglial activation, and neuronal apoptosis by regulating Nrf2/HO-1 and NF-kB signaling pathways. [13,14]ang et al [15,16] showed that it can also stimulate nerve growth factor (NGF) by regulating TrkA and PI3K/Akt signaling pathway, regulates autophagy-related cells, and promote myelin regeneration and axon regeneration, suggesting that curcumin can prevent Schwann cell apoptosis through autophagy, promote NGF, and promote myelination to accelerate the repair of rat sciatic nerve injury.Oxidative stress induced by a highglucose environment is one of the causes of DPN.Zhang et al [17] demonstrated that resveratrol stimulates the expression of Nrf2, inhibits the NF-KB pathway, and reduces the expression of neurofactors, including monocyte chemotactic protein-1 (MCP-1) and TNF-α and IL-1β, To protect peripheral nerves from apoptosis.Meng et al [18] demonstrated that resveratrol can inhibit NF-κB activity, reducing IL-6 and TNF-α and the expression of inflammatory factors such as COX-2.An experimental study showed that resveratrol was administered to Wistar rats for 6 weeks after STZ-induced diabetes, and after 6 weeks resveratrol treatment significantly reduced MDA, XO, and NO production and increased glutathione levels compared to the control group.Resveratrol is an effective neuroprotective agent against diabetic oxidative damage. [19]Studies have shown that resveratrol can inhibit the expression of TNF-α and IL-6 in the NF-κB signaling pathway and peripheral nerves, and activate the Nrf2/ARE signaling pathway to improve oxidative stress, increase sciatic nerve conduction velocity and intraneural blood flow in diabetic rats, and thus play a protective role in diabetic peripheral nerves. [20]Research shows.Polydatin [21] can improve mitochondrial function, reduce mitochondrial superoxide (mt SOX) by activating AMPK/PGC-1α pathway, and upregulate the expression of sirtuin (SIRT1), Nrf1, and m RNA.In terms of inflammation, polydatin has been shown to inhibit toll-like receptor-2 (TLR-2) and NF-κB p65 to reduce inflammatory cytokines. [22]A large number of scientific studies have reported that magnolol has antioxidant, anti-inflammatory, analgesic, neuroprotective, and other biological activities. [23]Yang et al [24] showed that magnolol inhibited apoptosis by inhibiting PPARγ/NF-κB signaling pathway, regulating Bcl-2 family proteins mediated by PPARγ in dorsal root ganglion and sciatic nerve of DPN rats, and promoting axon growth of DRG neurons.The mitochondrial basal respiration rate and ATP production of DPN mice were increased, the levels of MMP, mitochondrial complex I and IV (COX) were upregulated, and the mitochondrial bioenergy levels of DRG neurons of DPN mice were restored.

Terpenoids
Zhu et al [25] found that paeoniflorin interferes with SCs exosomes in a high-glucose environment, affecting the expression of proapoptotic protein in DRG neurons, increasing the expression of antiapoptotic protein, and reducing the apoptosis induced by endoplasmic reticulum stress to improve DPN.Yang et al [26] confirmed that paeoniflorin can reduce demyelination of sciatic nerve tissue and improve mechanical pain threshold by upregulating Trx reductase 2 (Trx2), indicating that paeoniflorin can improve mitochondrial function in high-glucose environments, which may be one of its mechanisms of protecting DPN nerve tissue.Zhang et al [27] studies have shown that tanshinone IIA can reduce pro-inflammatory factors (IL-1, TNFα, IL-6) and increase interleukin-(IL-)10, so as to reduce the excessive inflammatory response and protect peripheral nerves.Xu et al [28] demonstrated that andrographolide can accelerate the in vitro proliferation of RSC96 Schwann cells and maintain the phenotype of Schwann cells.Wang et al [29] have shown that Androgynous lotus can relieve abnormal pain caused by nerve injury, which may be closely related to the secretion of inflammatory factors.In cell experiments, loganin [30] has been confirmed to prevent RSC96 Schwann cell apoptosis by inhibiting ROS production, reducing the expression of NF-κB, P2 × 7 purinergic receptor (P2X7R), and thioredoxin-interacting protein (TXNIP), and inhibiting the activation of NOD-like receptor protein 3 (NLRP3) inflammatosome and the cleavage of gasdermin D (GSDMD), thus reducing peripheral nerve injury.

Saponins
Dioscin is a natural steroidal saponin, which plays an important role in the treatment of diabetes peripheral neuropathy.Research has found that diosgenin can improve NF-κB.Malondialdehyde (MDA), superoxide dismutase (SOD), TNF-α, IL-1β, thereby improving the antioxidant system. [31]Diosgenin inhibits the expression of COX-2 and iNOS in the sciatic nerve, indicating that diosgenin plays a repairing role in inflammatory damage to the sciatic nerve. [32]Research has shown that astragaloside IV can prevent mitochondrial dysfunction in central neurons by increasing SOD and glutathione (GSH), reducing MDA, inhibiting oxidative stress, and protecting peripheral nerves by regulating the SIRT1/p53 signaling pathway. [33]In addition, astragaloside IV promotes glutathione activity and increases advanced glycation end products (AGEs), thereby delaying peripheral nerve damage in streptozotocin (STZ) treated rats. [34]in et al [35] established in vitro and in vivo models and found that astragaloside IV can inhibit the expression of the PI3K/Akt/ mTOR signaling pathway, upregulates the expression of Beclin-1 and LC3 proteins, thereby reducing blood sugar in DPN rats and alleviating peripheral nerve damage.Ginsenoside is an extract of traditional Chinese medicine ginseng.Ginsenoside Rb1 can inhibit cell apoptosis and oxidative reactions in high-glucose environments.There are also studies indicating that the protective effect of ginsenosides on nerves may be related to mitochondrial dysfunction. [36]Glycyrrhetinic acid is the most abundant component in licorice.Studies by Ciarlo et al [37] have shown that ammonium glycyrrhetinic acid can inhibit SH-SY5Y cell apoptosis and mitochondrial dysfunction in high-glucose environments, and alleviate neuropathic hypersensitivity induced by STZ in DPN mice.

Alkaloid compounds
Berberine, also known as berberine, is the main active ingredient of Chinese herbal medicines such as Coptis chinensis and Phellodendron chinensis.As a natural activator of AMPK, it activates AMPK/PGC-1 by α pathway, upregulation of p-AMPK, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), The expression of Nrf1 improves mitochondrial biogenic defects, reduces ROS generation, and promotes the antioxidant defense system of Nrf2 to function. [38]Liu et al [39] showed that berberine can alleviate neuropathic pain caused by DPN, which is related to its inhibition of the expression of pro-inflammatory cytokines and TNF-α, IL-6, and IL-1β and related to iNOS and COX-2.Agoons et al [40] confirmed that local application of capsaicin can effectively alleviate pain caused by DPN in the second to 6th week after treatment, but this therapeutic effect will disappear after the 6th week.Some studies also suggest that the treatment of DPN with capsaicin is related to its concentration.High concentrations of capsaicin can inhibit the expression of the transient receptor potential vanilloid 1 (TRPV1), leading to long-term dysfunction of afferent nerve endings and achieving analgesic effects. [41]

Polysaccharides
Wang et al [42] intervened in high glucose-induced SCs by using water extracts of Aconite.After 48 hours of treatment, they found that aconite polysaccharides significantly reduced intracellular ROS, mainly manifested in upregulation of SOD, catalase (CAT), and PGC-1α.Downregulation of nicotinamide adenine dinucleotide phosphate oxidase-1 protein level at protein level significantly increases AMPK activation.Preliminary inference suggests that aconite polysaccharides may regulate AMPK/ PGC-1 by α The signaling pathway plays a protective role against high glucose-induced cell damage.Liu et al [43] showed that Lycium polysaccharide can inhibit the mTOR/p70S6K signaling pathway, increase the expression of sciatic nerve-related proteins (LC3-II, Beclin-1) in DPN rats, and inhibit P62 protein levels.This indicates that the protective effect of Lycium polysaccharide on DPN may be achieved by inducing autophagy.

Others
Salvianolic acid is considered the most abundant compound, and modern pharmacological studies have confirmed that salvianolic acid A (Sal A) and salvianolic acid B (Sal B) have antioxidant and antiapoptotic effects.Xu et al [44] found that Sal A can alleviate high glucose-induced damage by inhibiting 1,1-diphenyl-2-picrylhydrazine (DPPH) and reducing the levels of ROS, MDA, and oxidized glutathione (GSSG), as well as upregulating the expression of antioxidant enzyme mRNA, exhibiting strong antioxidant effects.Wang et al [45] confirmed that Sal B inhibited the expression of JNK pathway, the levels of apoptosis and autophagy-related proteins such as poly-ADPribose polymerase (PARP), cleaved caspase-3, cleaved caspase-9, Beclin-3, LC3-A/B were down-regulated.Inhibit apoptosis and autophagy, and have a protective effect on SCs in high-glucose environment.Achyranthes bidentata polypeptide K (ABPPk) is a compound of A. bidentata polypeptide.ABPPk has been shown to inhibit Schwann cell apoptosis by regulating the PI3K/AKT and ERK1/2 signaling pathways. [46]ABPPk is a light antioxidant active factor that needs to be further explored in the treatment of DPN and the prevention of neurological diseases.Melatonin is a hormone known to have the ability to resist oxidative stress.Tiong et al [47] found that melatonin can change NF-κB, Bcl-2, Wnt, and mTOR signals through antioxidant capacity, thereby reducing apoptosis of Schwann cells.

Summary and outlook
As of now, the pathogenesis of DPN has not been fully understood.Traditional Chinese medicine believes that its pathogenesis is related to dysfunction of the organs, phlegm stasis, and imbalance of qi, blood, yin, and yang.However, modern research suggests that it is caused by advanced glycation end products, oxidative stress, and mitochondrial disorders, activation of polyol pathways, nitration reactions, and endoplasmic reticulum stress.In recent years, scholars at home and abroad have demonstrated the mechanism of traditional Chinese medicine formulas and extracts in treating DPN, A large amount of basic research and clinical trials have been conducted, providing a significant theoretical basis for the prevention and treatment of DPN.The main signaling pathways involved in the treatment of DPN with traditional Chinese medicine formulas and monomers are NF-κB.The mechanisms involved in AMPK, Nrf2/ARE, JNK, miR-211, SIRT1/p53, etc, mainly include: controlling blood sugar, antioxidant, anti-inflammatory, inhibiting cell apoptosis, inhibiting autophagy, improving metabolic syndrome, etc.Each target is interconnected and jointly affects, exerting its protective effect on neuropathy.
Although many studies have not explicitly expressed the side effects of traditional Chinese medicine, the flexible application of traditional Chinese medicine has added challenges to the study of its mechanism for treating DPN.To better avoid the side effects of traditional Chinese medicine, research on the treatment of DPN with traditional Chinese medicine monomers is receiving increasing attention.This article reviews the protective effects of monomers, such as puerarin, baicalin, luteolin, paeoniflorin, and astragalus polysaccharides on DPN.The specific mechanism is detailed in Table 1.To translate the therapeutic potential of DPN into reality, it is necessary to increase experimental research on single traditional Chinese medicine or its monomers in the future.

Conclusions
In summary, by reviewing the research on the treatment of DPN with traditional Chinese medicine monomers, the key role of traditional Chinese medicine treatment has been clarified, providing new ideas for later clinical research and treatment.However, due to the large number of traditional Chinese medicine monomers, research on their treatment of DPN in various aspects is not thorough, resulting in some problems in their current research: the mechanism of traditional Chinese medicine treatment of DPN has not been integrated with traditional Chinese medicine theory; at present, traditional Chinese medicine monomers are widely used and mainly focused on animal experiments.However, the activation mechanisms are complex and diverse, and further cellular research is needed to confirm the exact target of action; the usage of traditional Chinese medicine in clinical practice is not clear, so its therapeutic effect is difficult to confirm.In the future, the efficacy, adverse reactions, and mechanism of action of traditional Chinese medicines, monomer drugs, and compounds can be summarized.On the one hand, the specific principle of their action on diseases can be more clearly understood.On the other hand, using methods such as component  omics, network pharmacology and molecular docking, bioinformatics, and high-throughput mass spectrometry, we explore the specific active ingredients of traditional Chinese medicine formulas and monomeric drugs entering the human body or other experimental animals.After specific research, we can seek benefits and avoid harm, and dismantle and verify the original classic formulas, which may make traditional Chinese medicine monomers more scientifically and effectively applied in clinical practice.

Table 1
Traditional Chinese medicine monomer therapy for diabetes peripheral neuropathy.